Stainless steel canister for propellant-driven metering aerosols

ABSTRACT

The present invention relates to corrosion resistant stainless steel canisters for propellant-containing aerosol forumlations for use in propellant gas-operated inhalers.

This application claims benefit of provisional application Ser. No.60/167,772 filed Nov. 29, 1999.

The present invention relates to corrosion-resistant stainless steelcanisters for propellant gas-containing aerosol formulations for use inpropellant gas-operated inhalers.

BACKGROUND OF THE INVENTION

In propellant-driven inhalers, the active substances are stored togetherwith the propellant in cartridge-like canisters. These canistersgenerally consist of an aluminium container sealed with an aluminiumvalve cup in which a valve is embedded. A canister of this kind can thenbe placed in the inhaler in the manner of a cartridge and is either leftthere permanently or replaced with a new cartridge after use. Sincechlorofluorocarbons (CFCs) were proscribed on the grounds of theirozone-destroying properties at the Rio de Janeiro Conference at thebeginning of the 90s, the use of fluorohydrocarbons (FHC) is promoted asan alternative for use in propellant-driven inhalers. The most promisingexample to date are TG 134a (1,1,1,2-tetrafluoroethane) and TG 227(1,1,1,2,3,3,3-heptafluoropropane). Accordingly, existing systems ofdelivery for treatments by inhalation have had to be converted toCFC-free propellants and new delivery systems and active substanceformulations have had to be developed.

Surprisingly, it has been found that aluminium canisters are not alwaysresistant to drug formulations containing fluorohydrocarbons aspropellants but have a high risk of corrosion depending on thecomposition of the formulations. This is particularly true offormulations which contain electrolytes and/or free ions, particularlyfree halides. In these cases, the aluminium is attacked, which meansthat aluminium cannot be used as a casing material for the canisters.Similar instabilities in the aluminium canisters have been observed whenfluorohydrocarbons are used as propellants if the formulations containacid or basic components, e.g. in the form of the active substances, theadditives, in the form of stabilisers, surfactants, flavour enhancers,antioxidants, etc.

DESCRIPTION OF THE INVENTION

One of the tasks of the present invention is to provide a canister forpropellant-driven inhalers which is corrosion-resistant in the presenceof active substance formulations for inhalation therapy containing afluorohydrocarbon as propellant, which has sufficient compressive andbreaking strength to withstand processing and use, which ensures thequality of the formulations stored therein and overcomes the otherdisadvantages known from the prior art.

The invention solves this problem by providing a canister forpropellant-driven inhalers which consists predominantly of an alloywhich is corrosion-resistant in the presence of drug formulationscontaining fluorohydrocarbons. The components of this alloy containchromium (Cr), nickel (Ni), molybdenum (Mo), iron (Fe) and carbon (C).In another embodiment the alloy additionally contains copper (Cu),manganese (Mn) and silicon (Si). The canister according to the inventionconsists of a container (2) and a valve cup (8) with valve (9). Thecontainer preferably consists of one of the alloys described below. Theinvention therefore also relates to a container of this kind.

The invention further relates to the use of a container or canister ofthis kind consisting of a container (2) and a valve cup (8) with valve(9) in propellant-operated metering aerosols (inhalers) and a processfor producing them.

The invention is hereinafter explained more fully with reference toFIGS. 1 and 2.

FIG. 1 shows the canister consisting of container (2), valve cup (8) andthe valve (9) in cross-section.

FIG. 2 shows another embodiment of the valve cup (8) and the valve (9)in cross-section.

FIG. 1 shows the canister (1) according to the invention incross-section. The canister (1) consists of a container (2) for holdingthe pharmaceutical formulation and a valve cup (8) with valve (9). Theshape and dimensions of the canister correspond to those of thealuminium canisters known from the prior art.

The container (2) according to the invention is made of an alloy havinga content of

Iron (Fe) of 40.0-53.0%,

Nickel (Ni) of 23.0-28.0%,

Chromium (Cr) of 19.0-23.0%,

Molybdenum (Mo) of 4.0-5.0%,

Manganese (Mn) of 0.0-2.0%,

Copper (Cu) of 1.0-2.0%,

Silicon (Si) 0.0-1.0%,

Phosphorus (P) 0.0-0.045%,

Sulfur (S) 0.0-0.035% and

Carbon (C) 0.0-0.020%.

This alloy is one according to the material number 1.4539 of thesteel-iron-list of the association of the German iron-works-worker (inGerman language: Werkstoffnummer der Stahl-Eisen-Liste des Vereinsdeutscher Eisenhüttenleute).

A preferred alloy of this type has the following composition:

Chromium (Cr) 19.0-21.0%,

Nickel (Ni) 24.0-26.0%,

Molybdenum (Mo) 4.0-5.0%,

Copper (Cu) 1.0-2.0%,

Manganese (Mn) up to 2.0%,

Silicon (Si) up to 0.5% and

Carbon (C) up to 0.02%, whereby the remainder consists essentially ofiron.

For a nearly identical alternative alloy the content of Molybdenum islimited to 4.5-5.0%.

In an alternative embodiment the container (2) according to theinvention consists of an alloy according to the material number 1.4404of the steel-iron-list of the association of the Germaniron-works-worker (in German language: Werkstoffnummer derStahl-Eisen-Liste des Vereins deutscher Eisenhüttenleute)consisting of

Iron (Fe) 60.0-72.0%,

Nickel (Ni) 9.0-13.0%,

Chromium (Cr) 17.0-21.0%,

Molybdenum (Mo) 2.0-3.0%,

Manganese (Mn) 0.0-1.5%,

Silicon (Si) 0.0-1.5%,

Phosphorus (P) 0.0-0.04%,

Sulfur (S) 0.0-0.04% and

Carbon (C) 0-0.03%.

Another embodiment of the canister (2) consits of an alloy consistingof:

Chromium (Cr) 16.5-18.5%,

Nickel (Ni) 11.0-14.0%,

Molybdenum (Mo) 2.0-2.5%,

Carbon (C) up to 0.03% and iron as the remaining component.

The alloys mentioned above are such that they are corrosion-resistant tovarious liquefied fluorohydrocarbons such as TG 134a(1,1,1,2-tetrafluoroethane) and TG 227(1,1,1,2,3,3,3-heptafluoropropane). These include propellant gasformulations having active substances suitable for inhalation therapy,surfactants, cosolvents, stabilisers, complexing agents, flavourcorrectors, antioxidants, salts, acids, bases or electrolytes, such ashydroxide ions, cyanide ions and/or halide anions such as fluoride,chloride, bromide or iodide.

The container (2) is formed from a casing made of one of the alloysdescribed above. The container (2) has four different zones: the flat orconcave, inwardly domed base (3), a cylindrical portion (4) which mergesinto the tapering neck (5) in its upper third and finally ends in thebead (6) which encircles the opening (7) of the container.

The wall thickness of the container (2) is between 0.1 and 0.5 mm in apreferred embodiment, preferably between 0.15 and 0.35 mm, mostpreferably about 0.19 to 3.0 mm.

In a preferred embodiment the container (2) will withstand a burstingpressure of more than 30000 hPa, preferably more than 100000 hPa, mostpreferably more than 200000 hPa. The weight of the container (2) is 5-15g in a preferred embodiment, 7-10 g in another and 7.9-8.7 g in yetanother. In an equally preferred embodiment the container (2) has avolume of 5 to 50 ml. Other containers have a volume of 10 to 20 mlwhilst still others have volumes of about 15-18 ml.

In the sealed state the container (2) is tightly sealed by means of thevalve cup (8) after being filled with the pharmaceutical formulation andthe propellant.

In another embodiment the valve cup (8) also consists of.corrosion-resistant material. Preferably this is one of the alloysdescribed above for the containers and/or a plastics material ofsuitable pharmaceutical quality.

In another embodiment the valve cup (8) consists of aluminium. In thiscase the seal (10) and/or the valve (9) are constructed so that thevalve cup (8) itself cannot come into contact with the liquid inside thecontainer.

A preferred embodiment of the valve cup (8) is as described in GB2324121, to which reference is hereby made.

In the closed state of the canister, the valve cup (8) is crimped aroundthe container (2) at its bead (6). In preferred embodiments a seal orgasket (10) seals the valve cup (8) relative to the bead (6). The sealmay be annular or disc shaped. It is preferably disc shaped. It mayconsist of materials known from the prior art which are suitable forusing pharmaceutical formulations with fluorohydrocarbons as thepropellants. Examples of suitable materials include thermoplasts,elastomers, materials such as neoprene, isobutylene, isoprene, butylrubber, buna rubber, nitrile rubber, copolymers of ethylene andpropylene, terpolymers of ethylene, propylene and a diene, e.g.butadiene, or fluorinated polymers. The preferred materials areethylene/propylene/diene terpolymers (EPDM).

On the side of the valve cup (8) facing the inside of the container, avalve (9) is formed so that the valve stem (12) passes through the valvecup (8) to the other side. The valve (9) sits in the central opening ofthe gasket (10) to form a seal. The gasket (10) and valve (9) togetherseal the valve cup (8) from the inside of the container, so that itcannot come into contact with the liquid in the container (2).

The valve (9) is constructed so that every element which is capable ofcoming into contact with the liquid inside the container (2) consists ofa material which is corrosion-resistant with respect to this liquid.Such elements include for example the spring or springs (11), the valvestem (12), which projects from the inside to the outside through theopening (17) in the valve cup (8), the metering chamber (13) and thevalve body (14). The spring (11) consists of steel, preferably astainless steel. The other elements of the valve (9) may consist, forexample, of steel, the alloy described above and/or a plastic. Theelements (12), (13) and (14) preferably consist of a plastic,particularly a polyester, most preferably polybutylene terephthalate.

As shown in FIG. 1, one or more other gaskets or seals, e.g. the gaskets(15) and/or (16), may be provided to prevent liquid or gas from escapingoutwards from the inside of the container. The gasket or gaskets may bearranged so that the liquid inside the container comes into contact onlywith the container jacket and the valve, apart from the actual gasket orgaskets.

The gasket (15) seals off the valve stem, which is optionally verticallymovable, at the point where it penetrates the valve cup (8). The gasket(16) seals the valve stem (12) inside the valve relative to the valvebody (14) and/or the metering chamber (13). In this way, the gaskets(15) and (16) prevent any liquid or gas from escaping from the interiorof the container along the outer casing of the valve stem and out of thecanister or from coming into contact with the valve cup by this route.The gaskets (15) and (16) may be made of the same material as the gasket(10), preferably an ethylene/propylene/diene terpolymer.

In one embodiment in which the valve cup (8) is not made of aluminiumbut of one of the corrosion-resistant materials described above, it isnot necessary for the gasket (10) together with the valve (9) to isolatethe valve cup completely from the inside of the container. Therefore, itis not necessary in this case for the gasket (10) and valve (9) to be insealing contact with one another. There may be a gap between the gasket(10) and the valve (9). In such a case the gasket (10) sits directly onthe underside of the valve cup (8), for example, and seals the edge ofthe valve cup (8) relative to the bead (6) on the container. The gasket(15) then seals the opening (17) in the valve cup (8) from the interiorof the container.

FIG. 2 shows another embodiment of the valve cup (8) with embedded valve(9). This embodiment is largely identical to that in FIG. 1. The majordifference is that the gasket (10) and the gasket (16) in the embodimentin FIG. 2 are combined to form one gasket (18). The gasket (18) enclosesthe underside of the valve plate (18). It is arranged so that the valvebody (14) is embedded in the gasket. The valve stem (12) passes throughthe gasket via the opening (19) which is located directly below theopening (17) in the valve cup (8). The opening (19) is of suchdimensions as to seal the valve stem (12) relative to the valve cup (8).The sealing material for the gasket (18) is identical to that describedfor the gasket (10).

The container (2) according to the invention is produced analogously tothe processes known from the prior art for producing aluminium canistersand the like, in which the container is stamped out of a sheet of thematerial in question, or the corresponding alloy. In the presentinvention, the container (2) is stamped out of a sheet of theabove-mentioned alloys of chromium (Cr), nickel (Ni), molybdenum (Mo),iron (Fe) and carbon (C) or from an alloy which additionally containscopper (Cu), manganese (Mn) and silicon (Si).

The container (2) or canister consisting of container (2) and valve cup(8) with valve (9) according to the invention is particularly suitablefor use with propellant gas formulations containing fluorohydrocarbons.Propellant gas formulations which can preferably be used in conjunctionwith the invention are disclosed in WO 94/13262, to which reference ishereby made. Particularly preferred formulations disclosed therein areacid-stabilised and/or ethanol propellant gas formulations containing1,1,2,2-tetrafluoroethane (TG 134a) and/or1,1,1,2,3,3,3-heptafluoropropane (TG 227) as the propellant gas,particularly those which contain ipatropium bromide, oxitropium bromide,albuterol, tiotropium bromide or fenoterol as active substance.

Depending on the active substance, inorganic or organic acids may beused as stabilisers. Examples of inorganic acids include, in addition tohalic acids and other mineral acids: sulphuric acid, hydrochloric acid,nitric acid or phosphoric acid, whilst examples of organic acids includeascorbic acid or citric acid. In the case of the salts of the activesubstances, the preferred acids are those wherein the anion is identicalto that of the salt of the active substance. Citric acid is generallysuitable for all active substances and their salts and is also mostpreferred.

The acid content is such that the pH of the formulation is between 1.0and 7.0, preferably between 2.0 and 5.0 and most preferably at about3.5. In the case of inorganic acids the preferred acid content is in therange from about 0.00002 to 0.01 N. In the case of ascorbic acid thepreferred content is roughly in the range from 0.0045 to 5.0 mg/ml andin the case of citric acid it is within the range from 0.0039 to 27.7mg/ml.

The formulations may additionally contain ethanol as cosolvent. Thepreferred amount is 1.0 to 50.0% by weight of the formulation.

The following are some preferred formulations by way of example whichcan be stored in a canister or a container of the type described above:

EXAMPLE 1

Ipatropium bromide monohydrate 0.001-2.5% by weight Absolute ethanol0.001-50% by weight TG 134a 50.0-99.0% by weight Inorganic acid0.01-0.00002 normal Water 0.0-5.0% by weight

EXAMPLE 2

Ipatropium bromide monohydrate 0.001-2.5% by weight Absolute ethanol0.001-50% by weight TG 134a 50.0-99.0% by weight Ascorbic acid0.00015-5.0 mg/ml purified water 0.0-5.0% by weight

EXAMPLE 3

Ipatropium bromide monohydrate 0.0187% by weight Absolute ethanol15.0000% by weight TC 134a 84.47730% by weight Citric acid 0.0040% byweight purified water 0.5000% by weight Total 100.0000% by weight

EXAMPLE 4

Ipatropium bromide monohydrate 0.0374% by weight Absolute ethanol15.0000% by weight TG 134a 84.4586% by weight Citric acid 0.0040% byweight purified water 0.5000% by weight Total 100.0000% by weight

EXAMPLE 5

Ipatropium bromide monohydrate 0.0748% by weight Absolute ethanol15.0000% by weight TG 134a 84.4212% by weight Citric acid 0.0040% byweight Purified water 0.5000% by weight Total 100.0000% by weight

EXAMPLE 6

Fenoterol hydrobromide 0.192% by weight Absolute ethanol 30.000% byweight TG 134a 67.806% by weight Citric acid 0.002% by weight Purifiedwater 2.000% by weight Total 100.0000% by weight

A method of filling the canisters with the corresponding formulationmight be, for example, the dual stage pressure fill method, the singlestage cold fill method or the single stage pressure fill method.

What is claimed is:
 1. A metered-dose inhaler having a metal cannisterto hold drug and non-CFC propellant gas, comprising the following alloyforming walls of the cannister: Iron comprising about 40.0 to about53.0%, Nickel comprising about 23.0 to about 28.0%, Chromium comprisingabout 19.0 to about 23.0%, Molybdenum of about 4.0 to about 5.0%,Manganese of about 0.0 to about 2.0%, Copper of about 1.0 to about 2.0%,Silicon of about 0.0 to about 1.0%, Phosphorous of about 0.0 to about0.045%, Sulfur of about 0.0 to about 0.035% and Carbon of about 0.0 toabout 0.020%.
 2. The metered-dose inhaler as recited in claim 1, whereinthe alloy is as follows: Chromium about 19.0 to about 21.0%, Nickelabout 24.0 to about 26.0%, Molybdenum about 4.0 to about 5.0%, Copperabout 1.0 to about 2.0%, Manganese about 0.0 to about 2.0%, Siliconabout 0.0 to about 0.5%, Carbon about 0.0 to about 0.02% and remainderIron.
 3. The metered-dose inhaler as recited in claim 1, wherein thecannister comprises a container and a valve cup with a valve embeddedtherein, the container constituting walls of the cannister.
 4. Themetered-dose inhaler as recited in claim 3, wherein the valve cup isaluminum and is sealed with a gasket relative to the interior of thecontainer.
 5. The metered-dose inhaler as recited in claim 3, whereinthe valve contains one or more stainless steel springs, a valve stem, ametering chamber and a valve body, wherein one or more of the valvestem, the metering chamber and the valve body are made of materialselected from steel, the alloy used for forming walls of the cannisterand a plastic.
 6. The metered-dose inhaler as recited in claim 5,wherein the springs are made of stainless steel, and the valve stem, themetering chamber and the valve body are made of polybutyleneterephthalate.
 7. The metered-dose inhaler as recited in claim 5,wherein the valve stem is sealed off from the valve cup by a gasket orgaskets.
 8. The metered-dose inhaler as recited in claim 7, wherein thegasket or gaskets are made from ethylene/propylene/diene terpolymer. 9.The metered-dose inhaler as recited in claim 5, wherein the valve cup ismade from the alloy used to form the container.
 10. The metered-doseinhaler as recited in claim 1, wherein walls of the canister canwithstand a bursting pressure of more than 30,000 hPa.
 11. Themetered-dose inhaler as recited in claim 10, wherein walls of thecannister can withstand a bursting pressure of more than 100,000 hPa.12. The metered-dose inhaler as recited in claim 10, wherein walls ofthe cannister can withstand a bursting pressure of more than 200,000hPa.
 13. The metered-dose inhaler as recited in claim 1, wherein wallsof the cannister are about 0.1 to about 0.5 mm thick.
 14. Themetered-dose inhaler as recited in claim 13, wherein walls of thecannister are about 0.15 to about 0.35 mm thick.
 15. The metered-doseinhaler as recited in claim 14, wherein walls of the cannister are about0.19 to about 0.30 mm thick.
 16. A metered-dose inhaler according toclaim 1, wherein the cannister contains a formulation comprising afluorohydrocarbon propellant.
 17. A metered-dose inhaler according toclaim 16, wherein the fluorohydrocarbon propellant is selected from1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.
 18. Ametered-dose inhaler according to claim 16, wherein the formulationfurther comprises one or more electrolytes.
 19. A metered-dose inhaleraccording to claim 16, wherein the formulation further comprises one ormore acids.
 20. A metered-dose inhaler according to claim 16, whereinthe formulation further comprises ethanol.
 21. A metered-dose inhalerhaving a metal cannister to hold drug and non-CFC propellant gas,comprising the following alloy forming walls of the cannister: Ironabout 60.0 to about 72.0%, Nickel about 9.0 to about 13.0%, Chromiumabout 17.0 to about 21.00%, Molybdenum about 2.0 to about 3.0%,Manganese about 0.0 to about 1.5%, Silicon about 0.0 to about 1.5%,Phosphorous about 0.0 to about 0.04%, Sulfur about 0.0 to about 0.04%and Carbon about 0.0 to about 0.03%.
 22. The metered-dose inhaler asrecited in claim 21, wherein the cannister comprises a container and avalve cup with a valve embedded therein, the container constitutingwalls of the cannister.
 23. The metered-dose inhaler as recited in claim22, wherein the valve cup is aluminum and is sealed with a gasketrelative to the interior of the container.
 24. The metered-dose inhaleras recited in claim 22, wherein the valve contains one or more stainlesssteel springs, a valve stem, a metering chamber and a valve body,wherein one or more of the valve stem, the metering chamber and thevalve body are made of material selected from steel, the alloy used forforming walls of the cannister and a plastic.
 25. The metered-doseinhaler as recited in claim 24, wherein the springs are made ofstainless steel, and the valve stem, the metering chamber and the valvebody are made of polybutylene terephthalate.
 26. The metered-doseinhaler as recited in claim 24, wherein the valve stem is sealed offfrom the valve cup by a gasket or gaskets.
 27. The metered-dose inhaleras recited in claim 26, wherein the gasket or gaskets are made fromethylene/propylene/diene terpolymer.
 28. The metered-dose inhaler asrecited in claim 24, wherein the valve cup is made from the alloy usedto form the container.
 29. The metered-dose inhaler as recited in claim21, wherein walls of the canister can withstand a bursting pressure ofmore than 30,000 hPa.
 30. The metered-dose inhaler as recited in claim29, wherein walls of the cannister can withstand a bursting pressure ofmore than 100,000 hPa.
 31. The metered-dose inhaler as recited in claim29, wherein walls of the cannister can withstand a bursting pressure ofmore than 200,000 hPa.
 32. The metered-dose inhaler as recited in claim21, wherein walls of the cannister are about 0.1 to about 0.5 mm thick.33. The metered-dose inhaler as recited in claim 32, wherein walls ofthe cannister are about 0.15 to about 0.35 mm thick.
 34. Themetered-dose inhaler as recited in claim 33, wherein walls of thecannister are about 0.19 to about 0.30 mm thick.
 35. A metered-doseinhaler according to claim 21, wherein the cannister contains aformulation comprising a fluorohydrocarbon propellant.
 36. Ametered-dose inhaler according to claim 35, wherein thefluorohydrocarbon is selected from 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoropropane.
 37. A metered-dose inhaler accordingto claim 35, wherein the formulation further comprises one or moreelectrolytes.
 38. A metered-dose inhaler according to claim 35, whereinthe formulation further comprises one or more acids.
 39. A metered-doseinhaler according to claim 35, wherein the formulation further comprisesethanol.
 40. A metered-dose inhaler having a metal cannister to holddrug and non-CFC propellant gas, comprising the following alloy formingwalls of the cannister: Chromium about 16.5 to about 18.5%, Nickel about11.0 to about 14.0%, Molybdenum about 2.0 to about 2.5%, Carbon about0.0 to about 0.03% and remainder Iron.
 41. The metered-dose inhaler asrecited in claim 40, wherein the cannister comprises a container and avalve cup with a valve embedded therein, the container constitutingwalls of the cannister.
 42. The metered-dose inhaler as recited in claim41, wherein the valve cup is aluminum and is sealed with a gasketrelative to the interior of the container.
 43. The metered-dose inhaleras recited in claim 41, wherein the valve contains one or more stainlesssteel springs, a valve stem, a metering chamber and a valve body,wherein one or more of the valve stem, the metering chamber and thevalve body are made of material selected from steel, the alloy used forforming walls of the cannister and a plastic.
 44. The metered-doseinhaler as recited in claim 43, wherein the springs are made ofstainless steel, and the valve stem, the metering chamber and the valvebody are made of polybutylene terephthalate.
 45. The metered-doseinhaler as recited in claim 43, wherein the valve stem is sealed offfrom the valve cup by a gasket or gaskets.
 46. The metered-dose inhaleras recited in claim 45, wherein the gasket or gaskets are made fromethylene/propylene/diene terpolymer.
 47. The metered-dose inhaler asrecited in claim 43, wherein the valve cup is made from the alloy usedto form the container.
 48. The metered-dose inhaler as recited in claim40, wherein walls of the canister can withstand a bursting pressure ofmore than 30,000 hPa.
 49. The metered-dose inhaler as recited in claim48, wherein walls of the cannister can withstand a bursting pressure ofmore than 100,000 hPa.
 50. The metered-dose inhaler as recited in claim48, wherein walls of the cannister can withstand a bursting pressure ofmore than 200,000 hPa.
 51. The metered-dose inhaler as recited in claim40, wherein walls of the cannister are about 0.1 to about 0.5 mm thick.52. The metered-dose inhaler as recited in claim 51, wherein walls ofthe cannister are about 0.15 to about 0.35 mm thick.
 53. Themetered-dose inhaler as recited in claim 52, wherein walls of thecannister are about 0.19 to about 0.30 mm thick.
 54. A metered-doseinhaler according to claim 40, wherein the cannister contains aformulation comprising a fluorohydrocarbon propellant.
 55. Ametered-dose inhaler according to claim 54, wherein thefluorohydrocarbon is selected from 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoropropane.
 56. A metered-dose inhaler accordingto claim 54, wherein the formulation further comprises one or moreelectrolytes.
 57. A metered-dose inhaler according to claim 54, whereinthe formulation further comprises one or more acids.
 58. A metered-doseinhaler according to claim 54, wherein the formulation further comprisesethanol.